Benefits of combined blockade may outweigh risks

Beaver Creek, CO-Urologists should not abandon combined androgen blockade as first-line therapy for metastatic prostate cancer, an expert in the disease told colleagues at the International Prostate Cancer Update here.

Combination therapy consists of medical or surgical castration plus a nonsteroidal antiandrogen. While castration results in a major decrease of testosterone, the androgen receptor can still be activated by residual testosterone, adrenal androgens, and ligand-independent activators.

Together, these trials gathered data on 8,275 men with metastatic or locally advanced prostate cancer. The results showed that maximum androgen blockade with nilutamide (Nilandron) or flutamide (Eulexin) slightly improves 5-year survival over androgen suppression alone (27.6% vs. 24.7%, p=.005). The use of cyproterone acetate (not available in the U.S.) was associated with a worse outcome.

Laurence Klotz, MD, and colleagues demonstrated a benefit of bicalutamide (Casodex) combination therapy versus castration alone when reviewing historical data from two large studies (ASCO 2004 annual meeting, abstract 4634). For the treatment of advanced prostate cancer, combination therapy using bicalutamide, 50 mg once daily, versus castration alone provided an estimated 20% reduction in the risk of death (hazard ratio =0.80). These results also suggest that there is a high probability (98.5%) that combination therapy using bicalutamide provides a survival advantage over castration alone.

"The study by Klotz demonstrates that bicalutamide, 50 mg once daily, in combination with androgen deprivation is a well-tolerated treatment option that provides a meaningful survival benefit for men with advanced disease," Dr. Vogelzang said.

A smaller study by Hideyuki Akaza, MD, randomized 205 men to either LHRH agonist therapy versus an LHRH agonist plus bicalutamide (Jpn J Clin Oncol 2004; 34:20-8). The results showed that PSA normalization at 12 weeks was 80% for men receiving combined androgen blockage versus 39% for those in the LHRH arm. The tumor response was 77% for the combined blockade arm and 65% for the LHRH arm. Time to failure and time to progression also favored combined blockade. Median follow-up was 15 months.

"While the results of this trial are impressive," Dr. Vogelzang explained, "this was a small trial conducted only on Japanese men. There is some concern about whether or not the results would be transferable to the American population."

Another study, RTOG 92-02, enrolled 1,514 men with advanced prostate cancer who were treated with the hormones goserelin acetate (Zoladex) and flutamide (Eulexin) plus radiotherapy. The hormones were given 2 months before and during radiotherapy.

For the long-term arm of the study, goserelin was given an additional 24 months following radiotherapy; no hormones were given after radiotherapy in the short-term arm. The results showed a slight survival advantage for men on long-term hormonal therapy.

"The trials are advocating combined androgen blockade," Dr. Vogelzang said. "I still think it's the right thing to do. The benefits outweigh the cost, in my opinion. If you remove flutamide, which was toxic, and cyproterone acetate, which was associated with a worse outcome in trials, then you are left with two drugs: nilutamide or bicalutamide.